Learning disabilities are among the more subtle, yet most pervasive, of fetal alcohol exposure-related defects in children. These learning deficits may not manifest until a child is school-aged and can occur in the absence of other physical evidence of alcohol-related birth defects. Deficits in hippocampal glutamatergic neurotransmission and synaptic plasticity have been observed in rats whose mothers consumed moderate quantities of ethanol during gestation. As glutamate receptor-dependent synaptic plasticity is important in learning, these defects are one candidate mechanism for the learning disabilities observed in offspring whose mothers drank moderate quantities of ethanol during pregnancy. The long-term objectives of our research program are two-fold: First, to more clearly delineate the neurobiological and behavioral mechanisms of activity-dependent synaptic plasticity deficits caused by prenatal ethanol exposure. Then, once these teratologic effects are better characterized, develop and explore rational treatment strategies for overcoming fetal ethanol exposure-induced learning deficits. The working hypothesis for this project states that: Prenatal ethanol exposure decreases metabotropic glutamate receptor (mGluR5)-mediated potentiation of amino acid transmitter release in dentate gyrus slices. In this proposal, we will focus on the initial steps in the process, the coupling of the mGluR5, the G-proteins Galphaq/11 and phospholipase C-beta1 (PLC-beta1) in the production of inositol 1, 4, 5 trisphosphate (IP3). The proposed deficit may be a function of: 1) Decreased mGluR5-coupled, phospholipase C (PLC)-stimulated IP3 production, which in turn, may result from 2) decreased levels of mGluR5, Galphaq/11 or PLC-beta1 proteins or 3) alterations in agonist-mediated desensitization of mGluR5-stimulated IP3 production. These studies will provide important new information about the effects of prenatal ethanol exposure on mGluR5 regulation of transmitter release, a critical component of synaptic plasticity in the hippocampal formation. Further, these results could provide insights into whether agents that affect mGluR function could be used to treat synaptic plasticity deficits and, ultimately, learning deficits in prenatal ethanol-exposed offspring.